The rapid development of molecular genetics has led to the identification of an increasing number of molecular abnormalities responsible for human diseases. Within the function unit constituted by the gene regions responsible for the expression of a biological signal and its regulation lie side by side. Each of these regions is liable to be the seat of pathological changes leading to a qualitative or quantitative abnormality of synthesis. The detection of these abnormalities allows screening for them but the major objective remains therapeutic.
The transfer of genes for therapeutic purposes or somatic “gene therapy” consists of inserting a “repairer” gene in the somatic cells of a constituted organism in order to compensate for the dysfunction of an endogenous gene; or even to add a novel function for a therapeutic purpose. The resulting genetic change is likely to be transmitted to the daughter cells of the manipulated cell but it will not be inherited. The normal counterpart of impaired DNA sequences is thus transformed into a medicine.
The field of gene therapy is today being very actively developed and combines clinical assays (for still very small patient populations) with very fundamental research work in to matters such as the modes of gene expression or the vectorization of the therapeutic nucleic acid sequences. The vectors presently used are derived either from inactivated viruses, such as retroviruses or adenoviruses, or macromolecular complexes. The retroviruses are more suitable for use in a target tissue comprising a contingent of stem cells capable of being manipulated ex vivo; on the other hand, when the target tissue is constituted of terminally differentiated cells or intimately enmeshed in an organ whose architectural constraints have major functional consequences, such as the lung, the transfer of genes must be performed in vivo, for example by means of adenoviruses. Gene therapy finds applications in diseases as diverse as hereditary diseases due to the alteration of a single gene, such as Duchenne's myopathy, lysosomal diseases, mucoviscidosis or acquired diseases such as AIDS, cancers, thrombo-embolic disease or degenerative neurological diseases, constitutional hematological diseases.
Nonetheless, although the potential applications of gene transfer are extraordinarily large, the therapeutic developments of this approach and its appropriateness still cone up against technological difficulties.
In this connection, the development of retroviral vectors more efficacious than the existing tools constitute a major objective. In fact, the retroviral vectors have demonstrated their efficacy in systems in which the target cells of the transfer are classically the subject of mitoses and ideally involve a contingent of stem cells; but the limitations are linked essentially to inadequate infectivity of the viruses used and/or a too moderate level of transcription. For this purpose useful vectors may be selected by considering in particular their infective titer.